NAT BME: The transient dilution of hydrogel microsphere inactivation coagulation factor in in-body blood purification

Blood purification can be carried out using in vitro methods, which are pumped out by various devices or techniques and then re-integrated into the blood circuit in the body.
surgery has become a key and life-saving treatment for end-stage kidney disease, liver failure and acute poisoning.
anticoagulant plays a fundamental role in the clinical blood purification process.
in the blood purification process, in order to keep the filters and circuits open, adequate anticoagulant treatment is usually required without the risk of excessive bleeding.
, determining the exact dose of anticoagulants is complex due to patient variability, and the clearance rate of anticoagulants in these patients varies depending on the state of the disease.
During blood purification, patients who overdose with anticoagulants may experience hemorrhagic complications such as cerebral hemorrhage and severe gastrointestinal bleeding, while patients who are underdoseing anticoagulants may experience clotting-related complications, including thrombosis in blood vessels, leading to circuit failure and early termination of treatment.
A variety of anticoagulants, such as common heparin, low molecular heparin, direct coagulase inhibitors (e.g. agagluent and otterin) and heparin (e.g. sulda sodium and Danaparin) are widely used to achieve systemic anticoagulants and avoid thrombosis in in vitro circulation, the use of traditional anticoagulants in blood purification is a low safety strategy, the risk of bleeding after blood purification and other key issues remain unresolved.
core problem of the current anticoagulant strategy is that water-soluble anticoagulants reflow back into the body in the blood, delaying the recovery of hemostotting function.
, local blood dilution using materials that only come into contact with blood in vitro circulation may be a highly safe strategy.
, we propose a temporary blood dilution strategy where polymer microspheres are used to bind coagulation factors in in vitro circulation rather than traditional anticoagulants.
When placed in the barrel, these polymer microspheres exhibit excellent stability and effectively bind to coagulation factors VIII, IX and XI;
in vitro circulation, blood is imported into a new device, followed by a hemodialysis unit or blood perfusion device, to achieve simultaneous anticoagulation, removal of endogenetic toxins and discharge of fluids.
haemophilia is caused by a lack of coagulation factors such as VIII, IX or XI.
this in-body blood thinning strategy as a pseudo-haemophilia model.
long-term deficiency of coagulation factors in patients with haemophilia, the partial deficiency of coagulation factors in false haemophilia models is temporary and local.
the blood was purified, the blood from fake haemophilia quickly returned to normal after it was re-injected into the patient.
to prevent accidental exposure to hydrogel balls, hydrogel balls are designed to be in the micron range and prepared by electrospray in accordance with our previous work 21.
to the hydrogel 3D (3D) network to provide blood dilution.
, in order to increase the dimensional stability of the hydrogel, a hydrophobic polymer skeleton is introduced into the hydrogel network.
choose polyethers with good stability, high mechanical strength and good film-forming properties widely used for blood purification as skeletons, adding N-vinyl-2-pyridoxine to enhance the hydrothermability of the skeleton, so that it is fully in contact with the blood.
In order to explore the optimal proportion of the two polymers in the hydrogel network, various microballs with different hydrogel networks were prepared and indicated by energy dispersion spectra, elemental analysis, and X-ray photoelectronic energy spectrum.
a series of gel experiments to determine the optimal composition of the consumption factor hydrogel network.
further study, called enhanced anticoagulant gel microballs (RAHMs), was conducted at a minimum concentration to extend the clotting time from 5 minutes to more than 180 minutes.
hydrophobic polymer microglomers (HPMs) show higher albumin adsorption levels than RAHMs, indicating good blood compatible.
the effects of RAHMs on plateplate adhesion were systematically studied by measuring plateplate adhesion levels and the concentration of plateboard factor 4 (PF4).
PF4 was not significantly different from that of the control group after RAHM was incubated in whole blood.
RAHM's red blood cell compatibness was studied using hemolytic experiments.
the above experiments show that the effects of microcells on blood cells are negligible and can therefore be safely used for treatment.
select human complement fragments 3a (C3a) and C5a as representative allergic toxins to assess the effects of RAHM on the complement activation system.
found that RAHMs do not induce the activity of the kinetic peptide-releasing enzyme-kinetic peptide system and inhibit the production of TAT when in contact with the blood.
addition, the antibacterial adhesion properties of RAHM have been studied, and it is difficult to observe that obvious bacteria adhere to the surface of RAHM, indicating that long-term preservation of RAHM is possible.
RAHMs are used to effectively absorb coagulation factors.
heparin, heparin has a strong and wide-ranging anticoagulant effect, and RAHMs have obvious targeted inhibition effect on endogenal coagulation factors, especially coagulation factor VIII.
factor VIII plays an important role in the coagulation cascading reaction because it can accelerate the activity of factor X by more than 200,000 times by synergizing with factor IXa, plateplate phospholipids, and factor III of damaged plate plate.
when factor VIII is in short supply, the steps to activate factor X are insufficient, which in turn leads to the risk of bleeding.
factor VIII is lacking in haemophilia A patients, also known as hemophilia factor.
although haemophilia-induced haemorrhagic episodes can be fatal, this condition is due to in-body blood purification circuits, as both anticoagulant and bleeding are caused by a lack or abnormality of coagulation factors.
, the fake haemophilia model avoids the risk of blood clotting in in vitro circulation, but the lack of coagulation factors is restored when blood is re-imported into the body.
addition, RAHM is a micro-ball and the RAHM device is designed as an perfusion column so that it is not exposed to the body, thus avoiding the risk of bleeding and the kidney metabolism of anticoagulants in the body circuit.
in vitro and in big dogs, hydrogel microspheres that absorb clotting factors VIII, IX, and XI are placed in in vitro circuits before blood purification, providing short-term blood dilution.
levels of microcosm inhibition of coagulation factor activity (-8-30%) were similar to mild haemophilia.
when reintroduced into animals, purified fake haemophilia blood helps stop bleeding faster.
choose not to actively supplement the coagulation factor after treatment, but to rely on the patient to reconstruct the coagulation factor, for the following reasons.
(1) Reconstructing coagulation factors from the patient's own storage pool avoids the cost and potential dangers of using clotting factor concentrates.
(2) coagulation factor VIII is expected to be updated every 1-2 days in the body due to its short half-life.
taking into account that the frequency of blood purification is approximately 3-4 days, even if all factor VIII is inactivated by RAHMs, treatment is safe because there is no anticoagulant in the body circuit and fake haemophilia blood can automatically accept the clotting factor.
, however, long-term studies are needed to confirm the safety of this method;
(3) It is important that the activity of the coagulation factor is reduced to only about 8-30%, which is the level of mild haemophilia.
mild haemophilia is one of the main forms of haemophilia, defined as clotting factor activity levels between 5% and 40% of normal levels.
mild haemophilia is usually not associated with spontaneous bleeding, and almost all incidents are caused by accident or surgery.
cases of haemophilia, although the level of coagulation factor is low, no additional coagulation factor treatment is usually required.
, within 120 minutes of the end of the experiment, the coagulation factor levels quickly returned to normal levels of 80-90%.
, the low coagulation factor levels achieved in our strategy are temporary and safe for patients, even those with limited ability to reconstruct clotting factors.
(4) The inhibitory coagulation factors in this strategy are factor VIII, IX, XI and XII, all of which are produced in the liver.
These coagulation factors have different half-lifes and circulate mainly inactive forms in the blood;
, the strategy of diluting blood into in vitro circulation can effectively reduce the risk of bleeding.
models showed greater safety than other anticoagulant strategies.
Song, X., Ji, H., Li, Y. et al. Transient blood thinning during extracorporeal blood purification via the inactivation of coagulation factors by hydrogel microspheres. Nat Biomed Eng(2021). MedSci Original Source: MedSci Original Copyright Notice: All text, images and audio and video materials on this website that indicate "Source: Mets Medicine" or "Source: MedSci Original" are owned by Mets Medicine and are not authorized to be reproduced by any media, website or individual, and are authorized to be reproduced with the words "Source: Mets Medicine".
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